WO2023159087A1 - Composés quinazoline et leur utilisation en tant qu'inhibiteurs de protéines kras mutantes - Google Patents

Composés quinazoline et leur utilisation en tant qu'inhibiteurs de protéines kras mutantes Download PDF

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WO2023159087A1
WO2023159087A1 PCT/US2023/062688 US2023062688W WO2023159087A1 WO 2023159087 A1 WO2023159087 A1 WO 2023159087A1 US 2023062688 W US2023062688 W US 2023062688W WO 2023159087 A1 WO2023159087 A1 WO 2023159087A1
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Prior art keywords
cancer
fluoro
methoxy
quinazolin
pyrrolizin
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PCT/US2023/062688
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English (en)
Inventor
Ning Chen
Fabien EMMETIERE
Jeffrey Jackson
Xiaofen Li
Yunxiao Li
Francesco Manoni
Imelda HOT
Primali NAVARATNE
Rene Rahimoff
Andrew SMALIGO
John Stellwagen
Wei Zhao
Ryan Wurz
John Allen
Liping Pettus
Brian Lanman
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Amgen Inc.
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Publication of WO2023159087A1 publication Critical patent/WO2023159087A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • the present disclosure provides compounds having activity as inhibitors of mutant KRAS proteins.
  • This disclosure also provides pharmaceutical compositions comprising the compounds, uses and methods of treating certain disorders, such as cancer, including but not limited to non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
  • KRAS the Kirsten rat sarcoma viral oncogene homologue
  • KRAS protein has historically proven resistant to direct inhibition.
  • KRAS is a G-protein that couples extracellular mitogenic signaling to intracellular, pro- proliferative responses.
  • KRAS serves as an intracellular “on/off” switch. Mitogen stimulation induces the binding of GTP to KRAS, bringing about a conformational change which enables the interaction of KRAS with downstream effector proteins, leading to cellular proliferation.
  • GAPs GTPase-activating proteins
  • the present application is directed to compound of formula (I): or a pharmaceutically acceptable salt of said compound, wherein; is a single bond or a double bond; W is C, CH or N; X is CH 2 , O, S, S(O), S(O)(NR z ) or S(O) 2 ; n is 0, 1, 2, or 3; m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; each R x is hydroxyl, halogen, oxo, cyano, -N(R z ) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, 5-7 membered heteroaryl, -T-R y or two R x taken together with the same carbon
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable excipient.
  • a compound of Formula I, or a pharmaceutically acceptable salt of said compound, or the pharmaceutical composition as described herein for use in treating cancer e.g., NSCLC, colorectal cancer or pancreatic cancer.
  • embodiment 1 a compound of formula (I): or a pharmaceutically acceptable salt of said compound, wherein; is a single bond or a double bond; W is C, CH or N; X is CH 2 , O, S, S(O), S(O)(NR z ) or S(O) 2 ; n is 0, 1, 2, or 3; m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; each R x is hydroxyl, halogen, oxo, cyano, -N(R z ) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, 5-7 membered heteroaryl, -T-R y or two R
  • embodiment 2 is the compound according to embodiment 1, wherein Z is N.
  • embodiment 3 is the compound according to any one of embodiments 1-2, wherein L is -O-C 1-6 alkylene (e.g., -O-methylene-, -O-ethylene- or -O-n-propylene-) substituted with 0-2 occurrences of R 2 .
  • embodiment 4 is the compound according to embodiment 3, wherein L is -O-methylene substituted with 0 occurrences of R 2 .
  • embodiment 5 is the compound according to any one of embodiments 1-4, wherein R 1 is heterocycloalkyl optionally substituted with 0-3 occurrences of R 5 .
  • embodiment 6 is the compound according to embodiment 5, wherein R 1 is 7-(hexahydro-1H-pyrrolizine) substituted with 0-3 occurrences of R 5 .
  • embodiment 7 is the compound according to embodiment 6, wherein R 1 is 7-(hexahydro-1H-pyrrolizine) substituted with 0 occurrences of R 5 .
  • embodiment 8 is the compound according to embodiment 6, wherein R 1 is 7- (hexahydro-1H-pyrrolizine) substituted with 1 occurrence of R 5 .
  • embodiment 9 is the compound according to embodiment 8, wherein R 5 is halogen (e.g., fluorine).
  • embodiment 10 is the compound according to any one of embodiments 1-4, wherein R 1 is 2-pyrrolidine substituted with 0-3 occurrences of R 5 .
  • embodiment 11 is the compound according to embodiment 10, wherein R 1 is 2-pyrrolidine substituted with 2 occurrences of R 5 .
  • embodiment 12 is the compound according to embodiment 11, wherein one R 5 is C 1-4 alkyl (e.g., methyl) and the other R 5 is halogen (e.g., fluorine).
  • embodiment 13 is the compound according to embodiment 3, wherein L is -O- n-propylene substituted with 2 occurrences of R 2 .
  • embodiment 14 is the compound according to embodiment 13, wherein both R 2 are taken together on the same carbon atom to form a cyclopropyl.
  • embodiment 15 is the compound according to embodiment 14, wherein R 1 is hydroxyl.
  • embodiment 16 is the compound according to any one of embodiments 1-15, wherein -L-R 1 is or Provided herein as embodiment 17 is the compound according to embodiment 16, wherein -L-R 1 is .
  • embodiment 18 is the compound according to embodiment 16, wherein -L-R 1 is .
  • embodiment 19 is the compound according to embodiment 16, wherein -L-R 1 is .
  • embodiment 20 is the compound according to embodiment 16, wherein -L-R 1 is .
  • embodiment 21 is the compound according to embodiment 16, wherein -L-R 1 is Provided herein as embodiment 22 is the compound according to any one of embodiments 1-21, wherein R 3 is aryl (e.g., phenyl or naphthyl) substituted with 0-3 occurrences of R 6 .
  • embodiment 23 is the compound according to embodiment 22, wherein R 3 is naphthyl substituted with 1 occurrence of R 6 .
  • embodiment 24 is the compound according to embodiment 23, wherein R 6 is hydroxyl.
  • embodiment 25 is the compound according to embodiment 22, wherein R 3 is naphthyl substituted with 2 occurrences of R 6 .
  • embodiment 26 is the compound according to embodiment 25, wherein each occurrence of R 6 is halogen, hydroxyl, C 2-4 alkynyl or C 1-4 alkyl.
  • embodiment 27 is the compound according to embodiment 26, wherein each occurrence of R 6 is fluorine, hydroxyl, 2-ethynyl or ethyl.
  • embodiment 28 is the compound according to embodiment 22, wherein R 3 is naphthyl substituted with 3 occurrences of R 6 .
  • embodiment 29 is the compound according to embodiment 28, wherein each occurrence of R 6 is hydroxyl, C 2-4 alkynyl, C 1-4 alkyl, halogen or amino.
  • embodiment 30 is the compound according to embodiment 29, wherein each occurrence of R 6 is hydroxyl, 2-ethynyl, ethyl, fluorine, chlorine or amino.
  • embodiment 31 is the compound according to embodiment 22, wherein R 3 is phenyl substituted with 3 occurrences of R 6 .
  • embodiment 32 is the compound according to embodiment 31, wherein each occurrence of R 6 is halogen, hydroxyl, C 1-4 haloalkyl, C 3-7 cycloalkyl or amino wherein each C 3-7 cycloalkyl is further substituted with 0-3 occurrences of R 7 .
  • embodiment 33 is the compound according to embodiment 32, wherein each occurrence of R 6 is hydroxyl, chloro, cyclopropyl, trifluoromethyl or amino, wherein each cyclopropyl is further substituted with 0 occurrences of R 7 .
  • embodiment 34 is the compound according to embodiment 31, wherein each occurrence of R 6 is hydroxyl and the other two R 6 are on adjacent carbon atoms form a C 3-7 cycloalkyl, wherein C 3-7 cycloalkyl is further substituted with 0-2 R 7 .
  • embodiment 35 is the compound according to embodiment 34, wherein each occurrence of R 6 is hydroxyl and the other two R 6 are on adjacent carbon atoms form a cyclohexyl further substituted with one R 7 .
  • embodiment 36 is the compound according to embodiment 35, wherein R 7 is C 1-4 alkyl (e.g., methyl or ethyl).
  • embodiment 37 is the compound according to any one of embodiments 1-21, wherein R 3 is heteroaryl substituted with 0-3 occurrences of R 6 .
  • embodiment 38 is the compound according to embodiment 37, wherein R 3 is 4-(1H-indazolyl) or 7-(1H-indazolyl) substituted with 0-3 occurrences of R 6 .
  • embodiment 39 is the compound according to embodiment 38, wherein R 3 is 4-(1H-indazolyl) substituted with 0-3 occurrences of R 6 .
  • embodiment 40 is the compound according to embodiment 39, wherein R 3 is 4-(1H-indazolyl) substituted with 2 occurrences of R 6 .
  • embodiment 41 is the compound according to embodiment 40, wherein each R 6 is C 1-4 alkyl, C 2-4 alkenyl or halogen.
  • embodiment 42 is the compound according to embodiment 41, wherein each R 6 is cyclopropyl, methylcyclopropyl, cis-prop-1-enyl, methyl or chloro, wherein cyclopropyl is further substituted with one occurrence of R 7 .
  • embodiment 43 is the compound according to embodiment 42, wherein R 7 is C 1-4 alkyl (e.g., methyl).
  • embodiment 44 is the compound according to embodiment 38, wherein R 3 is 7-(1H-indazolyl) substituted with 0-3 occurrences of R 6 .
  • embodiment 45 is the compound according to embodiment 44, wherein R 3 is 7-(1H-indazolyl) substituted with 2 occurrences of R 6 .
  • embodiment 46 is the compound according to embodiment 45, wherein each R 6 is C 1-4 alkyl or halogen.
  • embodiment 47 is the compound according to embodiment 46, wherein each R 6 is methyl or chloro.
  • embodiment 48 is the compound according to any one of embodiments 1-47, wherein R 3 is
  • embodiment 49 is the compound according to embodiment 48, wherein R 3 is Provided herein as embodiment 50 is the compound according to embodiment 48, wherein R 3 is Provided herein as embodiment 51 is the compound according to embodiment 48,
  • R 3 is Provided herein as embodiment 52 is the compound according to embodiment 48, wherein R 3 is .
  • Provided herein as embodiment 53 is the compound according to embodiment 48, wherein R 3 is .
  • Provided herein as embodiment 54 is the compound according to embodiment 48, wherein R 3 is Provided herein as embodiment 55 is the compound according to embodiment 48, wherein R 3 is Provided herein as embodiment 56 is the compound according to embodiment 48, wherein R 3 is .
  • embodiment 57 is the compound according to embodiment 48, wherein R 3 is Provided herein as embodiment 58 is the compound according to embodiment 48, wherein R 3 is .
  • embodiment 59 is the compound according to embodiment 48, wherein R 3 is .
  • embodiment 60 is the compound according to embodiment 48, wherein R 3 is .
  • embodiment 61 is the compound according to embodiment 48, wherein R 3 is .
  • embodiment 62 is the compound according to embodiment 48, wherein R 3 is .
  • embodiment 63 is the
  • R 3 is Provided herein as embodiment 64 is the compound according to embodiment 48, wherein R 3 is .
  • Provided herein as embodiment 65 is the compound according to embodiment 48, wherein R 3 is Provided herein as embodiment 66 is the compound according to embodiment 48, wherein R 3 is .
  • Provided herein as embodiment 67 is the compound according to embodiment 48, wherein R 3 is Provided herein as embodiment 68 is the compound according to embodiment 48, wherein R 3 is Provided herein as embodiment 69 is the compound according to embodiment 48, wherein
  • R 3 is .
  • embodiment 70 is the compound according to embodiment 48, wherein R 3 is Provided herein as embodiment 71 is the compound according to embodiment 48, wherein R 3 is Provided herein as embodiment 72 is the compound according to any one of embodiments 1-71, wherein W is N.
  • embodiment 73 is the compound according to embodiment 72, wherein X is CH 2 .
  • embodiment 74 is the compound according to embodiment 73, wherein n is 1 and m is 0 or m is 1 and n is 0.
  • embodiment 75 is the compound according to embodiment 74, wherein p is 1.
  • embodiment 76 is the compound according to embodiment 75, wherein R x is hydroxy or -T-R y .
  • embodiment 77 is the compound according to embodiment 76, wherein R x is hydroxyor -C(O)NH 2 .
  • embodiment 78 is the compound according to embodiment 73, wherein n is 1 and m is 1.
  • embodiment 79 is the compound according to embodiment 78, wherein p is 2.
  • embodiment 80 is the compound according to embodiment 79, wherein each R x is independently hydroxy, C 1-4 alkyl, C 1-4 haloalkyl or two R x taken together with the same carbon or adjacent carbon atoms can form a 5-7 membered heterocycloalkyl further substituted with 0-3 occurrences of R y .
  • embodiment 81 is the compound according to embodiment 80, wherein each R x is independently hydroxy, methyl, fluoromethyl or difluoromethyl.
  • embodiment 82 is the compound according to embodiment 80, wherein two R x are taken together with the same carbon to form a 1-oxetanyl, 1-azetidinyl, 2-azetidinyl, 2-pyrrolidinyl, cyclobutyl, 1,3-dioxolanyl, 3- tetrahydrothiophenyl, 2-tetrahydrofuranyl or 5-oxazolidinyl further substituted with 0-3 occurrences of R y .
  • embodiment 83 is the compound according to embodiment 82, wherein two R x are taken together with the same carbon to form a 1-oxetanyl further substituted with 0 occurrences of R y .
  • embodiment 84 is the compound according to embodiment 82, wherein two R x are taken together with the same carbon to form a 1-azetidinyl, 2-azetidinyl, 2-pyrrolidinyl, 1,3-dioxolanyl, 2- tetrahydrofuranyl or 5-oxazolidinyl further substituted with 1 occurrence of R y .
  • embodiment 85 is the compound according to embodiment 84, wherein R y is oxo.
  • embodiment 86 is the compound according to embodiment 82, wherein two R x are taken together with the same carbon to form a cyclobutyl further substituted with 1 occurrence of R y .
  • embodiment 87 is the compound according to embodiment 86, wherein R y is hydroxyl.
  • embodiment 88 is the compound according to embodiment 82, wherein two R x are taken together with the same carbon to form a 3-tetrahydrothiophenyl further substituted with 2 occurrences of R y .
  • embodiment 89 is the compound according to embodiment 88, wherein both R y are oxo.
  • embodiment 90 is the compound according to embodiment 78, wherein p is 3.
  • embodiment 91 is the compound according to embodiment 90, wherein each R x is independently hydroxy, halogen, -N(R z ) 2 , -T-R y or two R x taken together form a bridged ring where the bridge is C 1-4 alkylene is further substituted with 0-2 occurrences of R y .
  • embodiment 92 is the compound according to embodiment 91, wherein two R x are fluorine and the other R x is -NH 2 .
  • embodiment 93 is the compound according to embodiment 91, wherein two R x are fluorine and the other R x is -T-R y .
  • embodiment 94 is the compound according to embodiment 93, wherein two R x are fluorine and the other R x is -NH-C(O)-OMe.
  • embodiment 95 is the compound according to embodiment 91, wherein one R x is hydroxy and two R x taken together form a bridged ring where the bridge is ethylene is further substituted with 0 occurrences of R y .
  • embodiment 96 is the compound according to embodiment 73, wherein n is 1 and m is 2 or n is 2 and m is 1.
  • embodiment 97 is the compound according to embodiment 96, wherein p is 3.
  • embodiment 98 is the compound according to embodiment 97, wherein one R x is hydroxyl and the other two R x taken together form a bridged ring where the bridge is -C 1-4 alkylene further substituted with 0-2 occurrences of R y .
  • embodiment 99 is the compound according to embodiment 98, wherein one R x is hydroxyl and the other two R x taken together form a bridged ring where the bridge is methylene further substituted with 0 occurrences of R y .
  • embodiment 100 is the compound according to embodiment 73, wherein Provided herein as embodiment 101 is the compound according to embodiment 100, wherein Provided herein as embodiment 102 is the compound according to
  • embodiment 100 wherein .
  • Provided herein as embodiment 103 is the compound according to embodiment 100, wherein Provided herein as embodiment 104 is the compound according to embodiment 100, wherein is Provided herein as embodiment 105 is the compound according to embodiment 100, wherein Provided herein as embodiment 106 is the compound according to embodiment 100, wherein Provided herein as embodiment 107 is the compound according to embodiment 100, wherein Provided herein as embodiment 108 is the compound according to embodiment 100, wherein .
  • Provided herein as embodiment 109 is the compound according to embodiment 100, wherein
  • embodiment 110 is the compound according to embodiment 100, wherein Provided herein as embodiment 111 is the compound according to embodiment 100, wherein Provided herein as embodiment 112 is the compound according to embodiment 100, wherein is, Provided herein as embodiment 113 is the compound according to embodiment 100, wherein s .
  • embodiment 114 is the compound according to embodiment 100, wherein .
  • embodiment 115 is the compound according to embodiment 100, wherein .
  • embodiment 116 is the compound according to embodiment 100, wherein is Provided herein as embodiment 117 is the compound according to embodiment 100, wherein .
  • embodiment 118 is the compound according to embodiment 100, wherein Provided herein as embodiment 119 is the compound according to embodiment 100, wherein is .
  • embodiment 120 is the compound according to embodiment 100, wherein Provided herein as embodiment 121 is the compound according to embodiment 100, wherein .
  • embodiment 122 is the compound according to embodiment 100, wherein is .
  • embodiment 123 is the compound according to embodiment 100, wherein Provided herein as embodiment 124 is the compound according to embodiment 100, wherein Provided herein as embodiment 125 is the compound according to embodiment 72, wherein X is O.
  • embodiment 126 is the compound according to embodiment 125, wherein n is 1 and m is 1.
  • embodiment 127 is the compound according to embodiment 126, wherein p is 2.
  • embodiment 128 is the compound according to embodiment 127, wherein two R x are taken together to form a bridged ring where the bridge is -C 1-4 alkylene further substituted with 0-2 occurrences of R y .
  • embodiment 129 is the compound according to embodiment 128, wherein two R x are taken together to form a bridged ring where the bridge is ethylene further substituted with 0 occurrences of R y .
  • embodiment 130 is the compound according to embodiment 125, wherein n is 1 and m is 2 or m is 1 and n is 2.
  • embodiment 131 is the compound according to embodiment 130, wherein p is 0.
  • embodiment 132 is the compound according to embodiment 130, wherein p is 2.
  • embodiment 133 is the compound according to embodiment 132, wherein each R x is halogen, hydroxyl, C 1-4 haloalkyl or C 1-4 alkyl or two R x are taken together to form a bridged ring where the bridge is -C 1-4 alkylene further substituted with 0-2 occurrences of R y .
  • embodiment 134 is the compound according to embodiment 133, wherein one R x is hydroxyl and the other R x is methyl.
  • embodiment 135 is the compound according to embodiment 134, wherein one R x is hydroxyl and the other R x is fluoromethyl.
  • embodiment 136 is the compound according to embodiment 133, wherein both R x are fluorine.
  • embodiment 137 is the compound according to embodiment 133, wherein two R x are taken together to form a bridged ring where the bridge is methylene further substituted with 0 occurrences of R y .
  • embodiment 138 is the compound according to embodiment 125, wherein Provided herein as embodiment 139 is the compound according to embodiment 138, wherein Provided herein as embodiment 140 is the compound according to embodiment 138, wherein , Provided herein as embodiment 141 is the compound according to embodiment 138, wherein Provided herein as
  • embodiment 142 is the compound according to embodiment 138, wherein Provided herein as embodiment 143 is the compound according to embodiment 138, wherein Provided herein as embodiment 144 is the compound according to embodiment 138, wherein Provided herein as embodiment 145 is the compound according to any one of embodiments 1- 144, wherein R 2 is hydrogen.
  • embodiment 146 is the compound according to any one of embodiments 1-144, wherein R 2 is halogen (e.g., fluorine).
  • embodiment 147 is the compound according to any one of embodiments 1-144, wherein R 2 is cyano.
  • embodiment 148 is the compound according to any one of embodiments 1-144, wherein R 2 is hydroxyl.
  • embodiment 149 is the compound according to any one of embodiments 1-144, wherein R 2 is amino.
  • embodiment 150 is the compound according to any one of embodiments 1- 149, wherein R 4 is halogen (e.g., fluorine).
  • embodiment 151 is the compound according to any one of embodiments 1-149, wherein R 2 is C 1-4 alkyl (e.g., methyl).
  • embodiment 152 is the compound according to any one of embodiments 1- 151, wherein R 7 is hydrogen.
  • embodiment 153 is the compound according to embodiment 1, wherein is the compound is a compound of formula (II):
  • embodiment 154 is the compound according to embodiment 1, wherein is the compound is a compound of formula (III):
  • embodiment 155 is the compound according to embodiment 1, wherein is the compound is a compound of formula (IV):
  • embodiment 156 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: (6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-
  • embodiment 157 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: (6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (5S)-7-(7-(8-(8-(
  • embodiment 158 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Isomer 1); (3R)-1-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (Isomer 2); 7-(7-(8-E
  • embodiment 159 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Isomer 1); (3R)-1-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (Isomer 2); 7-(7-(8-E
  • a pharmaceutical composition comprising a compound disclosed herein in combination with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants and the like, and, if desired, other active ingredients. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V.
  • a pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.
  • the compound(s) disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended.
  • compositions presented herein may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.
  • the pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension.
  • the pharmaceutical composition is typically made in the form of a dosage unit containing a particular amount of the active ingredient.
  • embodiment 160 is a pharmaceutical composition comprising the compound according to any one of embodiments 1-159, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.
  • embodiment 161 is a compound according to any one of Embodiments 1-159, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition according to embodiment 160 for use as a medicament.
  • the compounds described herein are to be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the foregoing or solvates of any of the foregoing. Accordingly, the scope of the methods and uses provided in the instant disclosure is to be understood to encompass also methods and uses employing all such forms.
  • the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. For example, animals including horses, dogs, and cats may be treated with compounds provided herein.
  • the disclosure provides methods of using the compounds or pharmaceutical compositions of the present disclosure to treat disease conditions, including but not limited to conditions implicated by KRAS G12D, G12V, G12A, G12S or G12C mutation (e.g., cancer).
  • the cancer types are non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
  • KRAS G12D mutations occur with the alteration frequencies shown in the table below (TCGA data sets; 1-3 For example, the table shows that 32.4% of subjects with pancreatic cancer have a cancer wherein one or more cells express KRAS G12D mutant protein. Accordingly, the compounds provided herein, which bind to KRAS G12D (see Section entitled “Biological Evaluation” below) are useful for treatment of subjects having a cancer, including, but not limited to the cancers listed in the table below.
  • Provided herein as embodiment 162 is a compound according to any one of embodiments 1-159 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 159 for use in treating cancer.
  • Embodiment 163 is a compound according to any one of Embodiments 1-159 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 159 for use in treating cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
  • Embodiment 164 is the compound or pharmaceutical composition for use of Embodiment 162 or 163, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small bowel cancer, appendiceal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small bowel cancer, appendiceal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal
  • Embodiment 165 is a use of the compound according to any one of Embodiments 1-159 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 160 in the preparation of a medicament for treating cancer.
  • Embodiment 166 is a use of the compound according to any one of Embodiments 1-159 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 160 in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
  • Embodiment 167 is the use according to Embodiment 165 or 166, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendoc
  • Embodiment 168 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of to any one of Embodiments 1-159 or a pharmaceutically acceptable salt thereof.
  • Embodiment 169 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of to any one of Embodiments 1-159 or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
  • Embodiment 170 is the method according to Embodiment 168 or 169, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendoc
  • Embodiment 171 is the method according to Embodiment 168 or 169, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
  • Embodiment 172 is the method according to Embodiment 171, wherein the cancer is non-small cell lung cancer.
  • Embodiment 173 is the method according to Embodiment 171, wherein the cancer is colorectal cancer.
  • Embodiment 174 is the method according to Embodiment 171, wherein the cancer is pancreatic cancer.
  • Embodiment 175 is the method according to anyone of Embodiments 170- 174, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12D, G12V, G12A, G12S or G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.
  • Combination Therapy The present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • such therapy includes but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.
  • chemotherapeutic agents include but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.
  • chemotherapeutic agents include but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.
  • Embodiment 176 is the method according to anyone of Embodiments 168- 175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK4/6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF-1R inhibitor, KIF18A inhibitor, MCL-1 inhibitor, MEK inhibitor, mTOR inhibitor, PD-1 inhibitor, PD-L1 inhibitor, PI3K inhibitor, Raf kinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agent.
  • the second compound is an Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK4/6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF-1R inhibitor, KIF
  • the second compound is administered as a pharmaceutically acceptable salt. In another embodiment the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • Aurora Kinase A Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor.
  • Aurora kinase A inhibitors for use in the methods provided herein include, but are not limited to, alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1-[(3-chloro-2- fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2- methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol- 3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N- (1-methylpiperidin-4-yl)-9H-pyrido[
  • AKT Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.
  • Exemplary AKT inhibitors for use in the methods provided herein include, but are not limited to, afuresertib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1-aminocyclobutyl)phenyl]-3- phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1-aminocyclobutyl)phenyl]-5- phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1-aminocyclobutyl)phenyl]-9- phenyl
  • Arginase Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.
  • Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidargistat and CB 280.
  • CDK4/6 Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4/6 inhibitor.
  • CDK 4/6 refers to cyclin dependent kinases (“CDK”) 4 and 6, which are members of the mammalian serine/threonine protein kinases.
  • CDK 4/6 inhibitor refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of CDK 4 and/or 6.
  • CDK 4/6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfony1)-4- piperidinyl]amino]).
  • the CDK4/6 inhibitor is palbociclib.
  • ErbB Family Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.
  • the term “ErbB family” as used herein refers to a member of a mammalian transmembrane protein tyrosine kinase family including: ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).
  • ErbB family inhibitor refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of at least one member of the ErbB family.
  • the modulation or inhibition of one or more ErbB tyrosine kinase may occur through modulating or inhibiting kinase enzymatic activity of one or more ErbB family member or by blocking homodimerization or heterodimerization of ErbB family members.
  • the ErbB family inhibitor is an EGFR inhibitor, e.g., an anti-EGFR antibody.
  • Exemplary anti-EGFR antibodies for use in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab, and cetuximab.
  • the anti-EGFR antibody is cetuximab.
  • the anti-EGFR antibody is panitumumab.
  • the ErbB family inhibitor is a HER2 inhibitor, e.g., an anti-HER2 antibody.
  • Exemplary anti-HER-2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.
  • the ErbB family inhibitor is a HER3 inhibitor, e.g., an anti-HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).
  • the ErbB family inhibitor is a combination of an anti-EGFR antibody and anti-HER2 antibody.
  • the ErbB family inhibitor is an irreversible inhibitor.
  • Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4- methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-propenamide)), PF 6274484 ((N-[4-[(3-chloro-4- fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 ((E)-N-[4-[3-chloro-4- [(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(d
  • the irreversible ErbB family inhibitor is afatinib. In one embodiment, the irreversible ErbB family inhibitor is dacomitinib. In one embodiment, the ErbB family inhibitor is a reversible inhibitor.
  • Exemplary reversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3- (trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3- methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H- pyrrolo
  • the reversible ErbB family inhibitor is sapitinib. In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.
  • ERK Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.
  • Exemplary ERK inhibitors for use in the methods provided herein include, but are not limited to, ulixertinib, ravoxertinib, CC-90003 (N-[2-[[2-[(2-methoxy-5-methylpyridin-4-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide), LY3214996 (6,6-dimethyl-2- [2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one), KO-947 (1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462, and JSI-1187.
  • FAK Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.
  • Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-N- methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]methanesulfonamide), VS-4718 (2-[[2-(2- methoxy-4-morpholin-4-ylanil
  • FGFR Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.
  • Exemplary FGFR inhibitors for use in the methods provided herein include, but are not limited to, futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5-dimethoxyphenyl)methoxy]pyrimidin- 2-yl]amino]pyrazol-1-yl]ethanol), AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4- [(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide), Debio 1347 ([5-amino-1-(2-methyl-3H-benzimidazol- 5-yl
  • Glutaminase Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.
  • Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.
  • IGF-1R Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.
  • IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, robatumumab, BMS-754807 ((2S)-1-[4-[(5- cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoropyridin-3-yl)-2- methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)- 2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.
  • KIF18A Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.
  • Exemplary KIF18A inhibitors for use in the methods provided herein include, but are not limited to, the inhibitors disclosed in US 2020/0239441, WO 2020/132649, WO 2020/132651, and WO 2020/132653, each of which is herewith incorporated by reference in its entirety.
  • MCL-1 Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.
  • MEK inhibitors for use in the methods provided herein include, but are not limited to, murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29-hexahydro-2,3,24,33-tetramethyl- 22H-9,4,8-(metheniminomethyno)-14,20:26,23-dimetheno-10H,20H-pyrazolo[4,3- l][2,15,22,18,19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), MIK 665 (( ⁇ R)- ⁇ -[[(5S)-5-[3- Chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl]oxy]-2-[[2-(2-(
  • the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is tapotoclax.
  • MEK Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is MEK inhibitor.
  • MEK inhibitors for use in the methods provided herein include, but are not limited to, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3- dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4- iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide), GDC-0623 (5-(2-fluoro- 4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro- 2-(2-fluoro-4-iodoanilino)-N-(2-hydroxye)
  • the MEK inhibitor is trametinib.
  • mTOR Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.
  • Exemplary mTOR inhibitors for use in the methods provided herein include, but are not limited to, everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, vistusertib, dactolisib, Torin-1 (1-(4-(4-propionylpiperazin-1-yl)-3- (trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one), GDC-0349 ((S)-1- ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl)phenyl)urea
  • the mTOR inhibitor is everolimus.
  • PD-1 Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.
  • Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and the anti-PD-1 antibody as described in US 10,640,504 B2 (the “Anti-PD-1 Antibody A,” column 66, line 56 to column 67, line 24 and column 67, lines 54-57), which is incorporated herein by reference.
  • the PD-1 inhibitor is pembrolizumab. In another embodiment the PD-1 inhibitor is the Anti-PD-1 Antibody A.
  • PD-L1 Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.
  • Exemplary PD-L1 inhibitors for use in the methods provided herein include, but are not limited to, atezolizumab, avelumab, durvalumab, ZKAB001, TG-1501, SHR-1316, MSB2311, MDX-1105, KN035, IMC-001, HLX20, FAZ053, CS1001, CK-301, CBT-502, BGB-A333, BCD-135, and A167.
  • the PD-L1 inhibitor is atezolizumab.
  • PI3K Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.
  • PI3K inhibitors for use in the methods provided herein include, but are not limited to, idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, dactolisib, voxtalisib, sonolisib, tenalisib, serabelisib, acalisib, CUDC-907 (N-hydroxy-2-[[2-(6- methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-
  • Raf Kinase Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.
  • RAF kinase refers to a member of a mammalian serine/threonine kinases composed of three isoforms (C-Raf, B-Raf and A-Raf) and includes homodimers of each isoform as well as heterodimers between isoforms, e.g., C-Raf/B-Raf heterodimers.
  • Raf kinase inhibitor refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Raf family kinases or is capable of disrupting Raf homodimer or heterodimer formation to inhibit activity.
  • the Raf kinase inhibitor includes, but is not limited to, encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a- dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide), Raf-709 (N-(2-methyl-5,-morpholino-6’-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3- (trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-
  • the Raf kinase inhibitor is encorafenib. In one embodiment, the Raf kinase inhibitor is sorafenib. In one embodiment, the Raf kinase inhibitor is lifirafenib.
  • SHP2 Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.
  • Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5- methylpyrazin-2-yl]methanol), TNO155, (3S,4S)-8-[6-amino-5-(2-amino-3-chloropyridin-4- yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine), and RMC-4630 (Revolution Medicine).
  • the SHP inhibitor for use in the methods provided herein is RMC-4630 (Revolution Medicine).
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3- dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2- oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652- 13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy-1- azet
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl- 4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin- 8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6- methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]
  • the SHP inhibitor for use in the methods provided herein is (1R)-8-[5-(2,3- dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78- 4).
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5- hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3- dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridine
  • the SHP inhibitor for use in the methods provided herein is 3-[(1R)-1-amino- 8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56- 5).
  • the SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in US 10,590,090 B2, US 2020/017517 A1, US 2020/017511 A1, or WO 2019/075265 A1, each of which is herewith incorporated by reference in its entirety.
  • SOS1 Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.
  • exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI 3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxolan-3- yl]oxyquinazolin-4-amine), and BI 1701963.
  • Src Kinase Inhibitors Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.
  • the term “Src kinase” as used herein refers to a member of a mammalian nonreceptor tyrosine kinase family including: Src, Yes, Fyn, and Fgr (SrcA subfamily); Lck, Hck, Blk, and Lyn (SrcB subfamily), and Frk subfamily.
  • Src kinase inhibitor refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Src kinases.
  • Exemplary Src kinase inhibitors for use in the methods provided herein include, but are not limited to, dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2- morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7- tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (1-(tert-butyl)-3-(p-tolyl)-1H
  • the Src kinase inhibitor is dasatinib. In one embodiment, the Src kinase inhibitor is saracatinib. In one embodiment, the Src kinase inhibitor is ponatinib. In one embodiment, the Src kinase inhibitor is vandetanib. In one embodiment, the Src kinase inhibitor is KX-01.
  • Chemotherapeutic Agents Provided herein is the method according to anyone of Embodiments 168-175, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agent.
  • chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folinate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate.
  • Stereoisomers may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E/Z)), enantiomers, diastereomers, and atropoisomers.
  • double-bond isomers i.e., geometric isomers (E/Z)
  • enantiomers e.e., diastereomers, and atropoisomers.
  • the scope of the instant disclosure is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form (for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure) and stereoisomeric mixtures (for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing) of any chemical structures disclosed herein (in whole or in part), unless the stereochemistry is specifically identified.
  • stereoisomerically pure form for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure
  • stereoisomeric mixtures for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated, unless otherwise noted. For example, represents and .
  • (4R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole represents (4R,5R)-4- methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole and (4R,5S)-4-methoxy-5-methyl-4,5,6,7-tetrahydro- 2H-isoindole.
  • the chemical name 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3- yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione represents (M)-7-chloro-6-fluoro-1-(2-isopropyl-4- methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and (P)-7-chloro-6-fluoro-1-(2-isopropyl- 4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
  • stereoisomer or “stereoisomerically pure” compound as used herein refers to one stereoisomer (for example, geometric isomer, enantiomer, diastereomer and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound.
  • a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of the compound.
  • a typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.
  • This disclosure also encompasses the pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compounds disclosed herein.
  • this disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized in accordance with methods well known in the art and methods disclosed herein. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents. Further, this disclosure encompasses pharmaceutical compositions comprising mixtures of any of the compounds disclosed herein and one or more other active agents disclosed herein.
  • isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of Formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium ( 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with isotopes such as deuterium ( 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be advantageous in some circumstances.
  • substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy.
  • PET Positron Emission Topography
  • Isotopically-labelled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying General Synthetic Schemes and Examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
  • Solvates As discussed above, the compounds disclosed herein and the stereoisomers, tautomers, and isotopically labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing may exist in solvated or unsolvated forms.
  • solvate refers to a molecular complex comprising a compound, or a pharmaceutically acceptable salt thereof as described herein and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules. If the solvent is water, the solvate is referred to as a “hydrate.” Accordingly, the scope of the instant disclosure is to be understood to encompass all solvents of the compounds disclosed herein and the stereoisomers, tautomers and isotopically labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing. Miscellaneous Definitions This section will define additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.
  • aryl refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms. Furthermore, the term “aryl” as used herein, refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together.
  • Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted with 1-4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S--- nitro, cyano, carboxy, alkyl-O-C(O)--, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, phenyl, and heterocyclyl.
  • substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroary
  • C 1-4 alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 4, and 1 to 6 carbon atoms, respectively.
  • Representative examples of C 1-4 alkyl or C 1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • C 1-4 alkylene and “C 1-6 alkylene” refer to a straight or branched divalent alkyl group as defined herein containing 1 to 4, and 1 to 6 carbon atoms, respectively.
  • alkylene examples include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec- butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene and the like.
  • C 2-4 alkenyl refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include both straight and branched moieties.
  • C 2-4 alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.
  • C 2-4 alkynyl refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon triple bond. The term includes both straight and branched moieties.
  • Representative examples of C 3-6 alkynyl include, but are not limited to, ethynyl, 1 -propynyl, 2- propynyl, 2-butynyl and 3-butynyl.
  • C 1-4 alkoxy or “C 1-6 alkoxy” as used herein refers to –OR # , wherein R # represents a C 1- 4 alkyl group or C 1-6 alkyl group, respectively, as defined herein.
  • Representative examples of C 1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.
  • Representative examples of C 1-6 alkoxy include, but are not limited to, ethoxy, propoxy, iso-propoxy, and butoxy.
  • C 3-8 cycloalkyl refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 8 carbons.
  • C 3-8 cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.
  • deutero as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with deuterium (“D” or “ 2 H”).
  • D deuterium
  • C 1-4 deuteroalkyl refers to a C 1-4 alkyl as defined herein, wherein one or more hydrogen atoms are substituted with D.
  • C 1-4 deuteroalkyl include, but are not limited to, -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CD 3 , -CDHCD 3 , -CD 2 CD 3 , -CH(CD 3 ) 2 , - CD(CHD 2 ) 2 , and -CH(CH 2 D)(CD 3 ).
  • halogen refers to –F, -CI, -Br, or -I.
  • halo as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with a halogen as defined herein.
  • C 1- 4 haloalkyl refers to a C 1-4 alkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen.
  • Representative examples of C 1-4 haloalkyl include, but are not limited to, -CH 2 F, -CHF 2 , - CF 3 , -CHFCl, -CH 2 CF 3 , -CFHCF 3 , -CF 2 CF 3 , -CH(CF 3 ) 2 , -CF(CHF 2 ) 2 , and -CH(CH 2 F)(CF 3 ).
  • heteroaryl refers to a 5-20 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N, O and S.
  • the heteroaryl is a 5-10 membered ring system (e.g., 5-7 membered monocycle, an 8-10 membered bicycle or a 11-14 membered tricycle) or a 5-7 membered ring system.
  • Exemplary monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5- pyrazinyl, 2-pyrazinyl, and 2-, 4-, and 5-pyrimidinyl.
  • Exemplary bicyclic heteroaryl groups include 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8- isoquinolinyl, 1-, 2-, 4-, 5-, 6-, 7-, or 8-benzimidazolyl and 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-indolyl.
  • heteroaryl also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings.
  • heterocycle refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states.
  • the heterocyclic group can be attached to a heteroatom or a carbon atom.
  • the heterocyclyl can include fused or bridged rings as well as spirocyclic rings.
  • heterocycles include tetrahydrofuran, dihydrofuran, 1, 4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, azetidine, thiazolidine, morpholine, and the like.
  • pharmaceutically acceptable refers to generally recognized for use in subjects, particularly in humans.
  • pharmaceutically acceptable salt refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-
  • excipient refers to a broad range of ingredients that may be combined with a compound or salt disclosed herein to prepare a pharmaceutical composition or formulation.
  • excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.
  • subject refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment the subject is a human.
  • therapeutically effective amount refers to that amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, a system, or subject that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • GENERAL SYNTHETIC PROCEDURES The compounds provided herein can be synthesized according to the procedures described in this and the following sections.
  • the compounds disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art. It should be appreciated that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any manner.
  • the compounds of Formula I can be synthesized according to the following schemes. Any variables used in the following schemes are the variables as defined for Formula I, unless otherwise noted. All starting materials are either commercially available, for example, from Merck Sigma-Aldrich Inc., Fluorochem Ltd, and Enamine Ltd. or known in the art and may be synthesized by employing known procedures using ordinary skill. Starting material may also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as, solvent, reaction temperature, and reagents, for the Schemes discussed in this section, may be found in the examples provided herein.
  • step A compound (I-1) is treated with an aliphatic alcohol, such as benzyl alcohol, and a base, such as Hunig’s base, or metal alkoxide, such as potassium tert-butoxide, in a solvent such as 1,4-dioxane to give compound (I-2).
  • step B compound (I-2) undergoes S N Ar reaction with a nucleophile having the formula R 1 -L-H in a solvent such as acetonitrile, in the presence of a base such as Hunig’s base, to give compound (I-3).
  • step C compound (I-3) is coupled with an organometallic reagent or a boronic acid (ester) to provide compound (I-4).
  • This coupling reaction proceeds in a solvent or mixture of solvents such as 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate.
  • step D compound (I-4) is treated with a suitable set of reagents, such as Pd/C with H 2 to remove the alkyl group R, giving compound (I-5).
  • Step E compound (I-5) is treated with an optionally substituted cyclic amine in the presence of coupling reagent such as HATU, and a base such as Hunig’s base, in a solvent such as DMA to give compounds of Formula (I).
  • coupling reagent such as HATU
  • Hunig’s base a base such as Hunig’s base
  • a solvent such as DMA
  • the species R 3 will contain protecting group(s), which can be removed in step D or after step E in the synthetic sequence.
  • step A compound (1) undergoes S N Ar reaction with an optionally substituted cyclic amine in a solvent such as dichloromethane and in the presence of a base such as Hunig’s base to give compound (I-10).
  • step B compound (I-10) undergoes S N Ar reaction with a nucleophile having the formula R 1 -L-H in a solvent such as acetonitrile, in the presence of a base such as Hunig’s base to give compound (I-11).
  • step C compound (I-11) is coupled with an organometallic reagent or a boronic acid (ester) to provide compounds of formula (I).
  • Preparative HPLC Method where indicated, the compounds described herein were purified via reverse phase HPLC using Waters FractionLynx or Gilson semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100 x 30 mm). A typical run through the instrument included: eluting at 45 mL/min with a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v formic acid) in water (0.1% formic acid) over 10 minutes; conditions can be varied to achieve optimal separations.
  • 1,4-oxazepan-6- one hydrochloride (0.30 g, 1.98 mmol, AA BLOCKS LLC), 4-methoxybenzyl chloride (0.37 g, 0.32 mL, 2.38 mmol, TCI America), DIPEA (0.77 g, 1.0 mL, 5.94 mmol, Sigma-Aldrich Corporation) and DCM (10 mL). The reaction was stirred at rt overnight.
  • Step 3 Chiral separation.4-(4-Methoxybenzyl)-6-methyl-1,4-oxazepan-6-ol (0.65 g, 2.59 mmol) was purified via SFC using a Chiralpak AD, 30 ⁇ 150 mm, 5 ⁇ m, column with a mobile phase of 20% methanol with 0.2% triethylamine using a flowrate of 200 mL/min to generate 246 mg of peak 1 with an ee of >99% and 292 mg of peak 2 with an ee of >99%.
  • Step 4 6-Methyl-1,4-oxazepan-6-ol hydrochloride.
  • Step 1 4-(Benzyloxy)-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazoline.7-Bromo-2,4-dichloro-8-fluoroquinazoline (92 mg, 0.31 mmol, PharmaBlock) was dissolved in acetonitrile (0.6 mL) and benzyl alcohol (0.34 g, 0.3 mL, 3.10 mmol) and DIPEA (0.12 g, 0.2 mL, 0.93 mmol) were added. The mixture was stirred at rt for 2 h.
  • the crude mixture was directly purified by column chromatography on silica gel, eluting with a gradient of 0 - 100% 3:1 EtOAc:EtOH in heptanes.
  • the product was redissolved in acetonitrile (0.6 mL), ((2R,7aS)-2- fluorohexahydro-1H-pyrro-7a-yl)methanol (49 mg, 0.31 mmol, LabNetwork) and DIPEA (0.12 g, 0.2 mL, 0.93 mmol) was added. The mixture was stirred at 80 °C overnight.
  • Step 2 4-(Benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoline.
  • Step 3 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol.
  • Step 1 4-(Benzyloxy)-7-bromo-2-chloro-6,8-difluoroquinazoline.7-Bromo-2,4-dichloro-6,8- difluoroquinazoline (1.00 g, 3.19 mmol, PharmaBlock) was dissolved in acetonitrile (12 mL) and benzyl alcohol (3.44 g, 3.3 mL, 31.9 mmol) and DIPEA (1.24 g, 1.7 mL, 9.56 mmol) were added. The mixture was stirred at 35 °C for 2 h.
  • Step 2 4-(Benzyloxy)-7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazoline.4-(Benzyloxy)-7-bromo-2-chloro-6,8-difluoroquinazoline (0.30 g, 0.77 mmol) was dissolved in acetonitrile (1.5 mL) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (0.12 g, 0.77 mmol) and DIPEA (0.30 g, 0.4 mL, 2.30 mmol) were added.
  • Step 3 4-(4-(Benzyloxy)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
  • Step 4 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol.
  • Step 1 Benzyl (S)-2-oxo-1-oxa-3,7-diazaspiro[4.5]decane-7-carboxylate.
  • Step 1 (R)-1-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol.
  • 7-bromo-2,4-dichloro-8-fluoroquinazoline (2.00 g, 6.76 mmol, Enamine)
  • acetonitrile 34 mL
  • 3R)-3-methylpiperidin-3-ol hydrochloride (1.08 g, 7.10 mmol, PharmaBlock) and DIPEA (2.62 g, 3.54 mL, 20.28 mmol, Sigma-Aldrich Corporation).
  • DIPEA 2.62 g, 3.54 mL, 20.28 mmol, Sigma-Aldrich Corporation
  • Step 2 (R)-1-(7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol.
  • Step 3 (R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3- methylpiperidin-3-ol.
  • Step 4 (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol.
  • Example 11 To a 10 mL round-bottom flask was added (3R)-1-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.20 g, 0.25 mmol) and cesium fluoride (76 mg, 0.50 mmol, Aldrich) in N,N-dimethylformamide (2.5 mL).
  • Step 2 4-(6-Amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol.7-(8-Ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-N-(4-methoxybenzyl)-4-(1,4-oxazepan-4-yl)quinazolin-6-amine was stirred in MeCN (2.3 mL) and HCl (4 M in 1,4
  • reaction was stirred at rt. After 30 min, the reaction was concentrated under reduced pressure and the resultant solid was suspended in DCM (1.3 mL) and 1,1,1-trifluoroacetic acid (0.2 mL, 2.24 mmol, Apollo Scientific Ltd.). The reaction was stirred at rt for 5 h.
  • reaction was then concentrated under reduced pressure, and purified sequentially via reverse phase HPLC and then by purification performed with 0.1% NH 4 OH in H 2 O and MeCN as mobile phase, XBridge column (19 x 100 mm, 5 Pm) to provide 4-(6-amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,4- oxazepan-4-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (6.1 mg, 0.01 mmol, 13 % yield) as yellow solid.
  • Step 1 (R)-1-(7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol.
  • 2,4,7-trichloro-8- fluoroquinazoline (1.00 g, 3.98 mmol, Enamine
  • DIPEA 2.06 g, 2.78 mL, 15.91 mmol, Sigma- Aldrich
  • Step 2 (R)-1-(8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol.
  • Step 3 (R)-1-(8-Fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3- methylpiperidin-3-ol.
  • Step 4 (R)-1-(7-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol.
  • Examples 48 to 50 Synthesized in an analogous manner to Example 47. Table 7. Analytical data for Examples 48 to 50. 6-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one (Example 51) 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol (30 mg, 0.06 mmol, Intermediate C) was dissolved in N,N-dimethylformamide (0.4 mL),
  • Step 1 rac-(1R,2S,5S)-8-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8- difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8- azabicyclo[3.2.1]octan-2-ol.
  • reaction was stirred at rt for 15 min, and then exo-azabicyclo[3.2.1]octan-2-ol hydrochloride (24 mg, 0.15 mmol, PharmaBlock) was added.
  • exo-azabicyclo[3.2.1]octan-2-ol hydrochloride 24 mg, 0.15 mmol, PharmaBlock
  • the reaction was stirred at rt for 16 h.
  • the reaction mixture was partitioned between water and ethyl acetate; the organic layer was separated and concentrated under reduced pressure.
  • Step 2 rac-(1S,5R)-8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8- azabicyclo[3.2.1]octan-2-ol.
  • Step 1 7-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7- diazaspiro[4.5]decan-2-one.
  • This compound was synthesized in an analogous manner to Example 55, using 1-oxa-3,7-diazaspiro[4.5]decan-2-one (CAS#: 1308384-36-2, ChemSpace).
  • Step 2 Chiral separation. 7-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8- difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7- diazaspiro[4.5]decan-2-one 2,2,2-trifluoroacetate (0.27 g, 0.33 mmol) was purified via SFC using a Chiralpak AD, 21 x 250 mm, 5 ⁇ m column with a mobile phase of 40% 2-propanol with 0.2% diethylamine using a flowrate of 80 mL/min to generate 37 mg of peak 1 with an ee of >99%, 66 mg of peak 2-3 and 34 mg of peak 4 with an e
  • Peak 2-3 was purified via SFC using a SS Whelk-O1, 21 x 250 mm, 5 ⁇ m column with a mobile phase of 40% methanol with 0.2% diethylamine using a flowrate of 80 mL/min to generate 25 mg of peak 2 with an ee >96% and 29 mg of peak 3 with an ee of >96%.
  • Step 3 7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7- diazaspiro[4.5]decan-2-one.
  • Isomers 1-4 were synthesized in an analogous manner to Example 55, using peak 1-4 from Step 2.
  • Isomer 1 Example 56: isolated as bis(2,2,2-trifluoroacetate), m/z (ESI): 666.0 (M+H) + .
  • Example 58 isolated as is bis(2,2,2-trifluoroacetate) salt, m/z (ESI): 666.0 (M+H) + .
  • Step 1 Chiral SFC separation of MOM-protected Intermediate D.2.6 g of material was purified using Chiralcel OD, 2 x 25 cm, 5 ⁇ m column with a mobile phase of 25% MeOH with 0.2% DEA using a flowrate of 120 mL/min to generate 1.18 g of peak 1 with an ee of 99% and 1.34 g of peak 2 with an ee of 96%. Peak assignment determined by SFC with Chiralcel OD column with 25% MeOH with 0.2% DEA. m/z (ESI): 528.2 (M+H) + .
  • Step 2 4-(6,8-Difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
  • Example 92 7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-7-azaspiro[4.5]decan-2-one (Example 92). This compound was prepared in a fashion similar to that described for Example 91 using 1-oxa-7- azaspiro[4.5]decan-2-one (CAS#: 1315303-69-5, PharmaBlock).
  • This compound was prepared in a fashion similar to that described for Example 91 using 1,3-dioxa-7- azaspiro[4.5]decan-2-one (CAS#: 2386032-05-7, Enamine). Chiral separation was performed prior to the deprotection step.
  • the sample was purified via SFC using a ChiralPak IC, 2 x 25 cm, 5 ⁇ m column with a mobile phase of 50% iPrOH with 0.2% DEA using a flowrate of 80 mL/min to generate 46 mg of peak 1 and 2 and 44 mg of peak 3 and 4. Peak assignment determined by SFC with ChiralPak IC column with 50% iPrOH with 0.2% DEA.
  • Step 2 The sample was purified via SFC using a (S,S) Whelk-O, 2 x 25 cm, 5 ⁇ m column with a mobile phase of 45% iPrOH with 0.2% DEA using a flowrate of 80 mL/min to generate 20 mg of peak 1 with an ee of 99% and 20 mg of peak 2 with an ee of 99%. Peak 2 gave the desired product.
  • Chiral separation was performed prior to the deprotection step.
  • the sample was purified via SFC using a Chiralcel OJ, 2 x 25 cm, 5 ⁇ m column with a mobile phase of 20% EtOH with 0.2% DEA using a flowrate of 80 mL/min. to generate 164 mg of peak 1 and 2 with an ee of 91%, 31 mg of peak 3 with an ee of 91% and 30 mg of peak 4 with an ee of 95%. Peak 4 gave the desired product.
  • Step 1.8-Bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol To a 50-mL round-bottomed flask was added 8-bromo-3,4-dihydronaphthalen-1(2H)-one (0.72 g, 3.2 mmol, Ambeed, Inc.) and lanthanum(III) chloride bis(lithium chloride) complex solution (0.6 M in THF, 5.3 mL, 3.2 mmol, Sigma- Aldrich Corporation) in THF (12.8 mL).
  • the crude material was purified by chromatography through a silica gel column (12 g), eluting with a gradient of 0 - 20% EtOAc in heptane, to provide 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalene (0.39 g, 1.63 mmol, 87 % yield) as colorless oil.
  • Step 4.4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol To a 50-mL round-bottomed flask was charged with 2-(4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.20 g, 0.55 mmol) in tetrahydrofuran (1.6 mL) and water (0.55 mL). At 0 °C, hydrogen peroxide (0.5 mL, 4.93 mmol) was slowly added, followed by addition of acetic acid (1.6 mL, 27.4 mmol).
  • Step 5.4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl pivalate To a 50-mL round- bottomed flask was added 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol (0.12 g, 0.47 mmol) and triethylamine (0.16 mL, 0.94 mmol) in tetrahydrofuran (2.4 mL). At 0 °C, 2,2-dimethylpropionyl chloride (87 ⁇ L, 0.71 mmol) was added slowly. The reaction mixture was stirred at 0 °C for 1 h.
  • Step 1 4-(6,8-Difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-yl trifluoromethanesulfonate.
  • Step 2 (3R)-1-(7-(3-Amino-8-ethyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol.
  • Step 3 Chiral separation. 70 mg sample was purified via SFC using a Chiralcel OJ, 21 x 250 mm, 5 ⁇ m column with a mobile phase of 20% MeOH using a flowrate of 100 mL/min to generate 19 mg of peak 1 with an ee of >99% and 20 mg of peak 2 with an ee of >99%. Peak 1 (Example 61): m/z (ESI): 624.3 (M+H) + .
  • Step 1 (3R)-1-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol.
  • Peak 1 (isomer 1, Example 66): m/z (ESI): 605.2 (M+H) + .
  • HATU 43 mg, 0.11 mmol, Combi-Blocks Inc.
  • 3-(difluoromethyl)piperidin-3-ol hydrochloride 23 mg, 0.12 mmol, Enamine
  • Step 1.4-Bromo-6-chloro-1-(triisopropylsilyl)-1H-indazole A vial was charged with 4-bromo- 6-chloro-1H-indazole (2.00 g, 8.64 mmol, CombiBlocks Inc.) and tetrahydrofuran (3.0 mL). The reaction mixture was then cooled to -78 °C. LiHMDS (1.0 M in THF, 10.4 mL, 10.4 mmol) was added dropwise, and the mixture was stirred for 20 min at -78 °C.
  • Triisopropylchlorosilane (2.00 g, 2.2 mL, 10.4 mmol) was added dropwise, and the mixture was stirred for 20 min at -78 °C before warming to rt. Upon completion (as indicated by TLC), the reaction was carefully quenched by the addition of water. The aqueous layer was extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 2.4-Bromo-6-chloro-5-iodo-1-(triisopropylsilyl)-1H-indazole A vial was charged with 4-bromo-6-chloro-1-(triisopropylsilyl)-1H-indazole (2.00 g, 5.16 mmol) and tetrahydrofuran (26 mL) under nitrogen.
  • reaction mixture was then cooled to -78 °C.
  • LDA 1.0 M in THF, 6.7 mL, 6.7 mmol
  • a solution of iodine (1.70 g, 6.70 mmol) in THF (1.0 mL) was then added dropwise, and the reaction was warmed to rt with stirring while monitoring via LCMS.
  • the reaction was quenched with 10% aqueous sodium thiosulfate solution.
  • the aqueous layer was extracted with DCM, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered.
  • Step 1 rel-4,4,5,5-Tetramethyl-2-((1R,2S)-2-methylcyclopropyl)-1,3,2-dioxaborolane.
  • dichloromethane (19.8 mL) in a 100 mL round-bottomed flask was added diethylzinc (1.0 M in hexane, 10.4 mL, 10.4 mmol).
  • diethylzinc 1.0 M in hexane, 10.4 mL, 10.4 mmol
  • the mixture was allowed to stir at 0 °C for 10 min, and then diiodomethane (2.79 g, 0.84 mL, 10.41 mmol) was added dropwise.
  • Step 1 6-Chloro-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate O).
  • Step 1 rel-4-Bromo-6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2- yl)-1H-indazole.
  • Step 2 6-Chloro-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. rel-4-Bromo-6-chloro-5-((1R,2S)-2- methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.20 g, 3.30 mmol) was dissolved in THF (16 mL) and cooled to -78 °C.
  • the sample (9.5 g) was purified via SFC using a Chiralpak AD, 30 x 250 mm, 5 ⁇ m, column with a mobile phase of 20% 2-propanol using a flowrate of 150 mL/min to generate 3.58 g of peak 1 with an ee of >99%, and 5.02 g of peak 2 with an ee of >99%. Peak 2 yielded the desired isomer.
  • Step 1 (Z)-4-Bromo-6-methyl-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole.
  • a vial was charged with potassium phosphate tribasic (3.53 g, 16.6 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium dichloride (0.35 g, 0.48 mmol), 4,4,5,5-tetramethyl-2-[(z)- prop-1-enyl]-1,3,2- dioxaborolane (1.1 mL, 5.7 mmol, PharmaBlock ), 4-bromo-5-iodo-6-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole (2.00 g, 4.75 mmol), water (3.2 mL) and 1,4-dioxane (16 mL).
  • Step 2 (Z)-6-Methyl-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.
  • (Z)-4-bromo-6-methyl-5-(prop-1-en-1-yl)-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole (1.03 g, 3.08 mmol) was dissolved in tetrahydrofuran (40 mL) and cooled to -78 °C.
  • Peak 2 was desired isomer (S)-6-(7- bromo-2-chloro-8-fluoroquinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane.
  • Step 1 (R)-1-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol.
  • reaction mixture was purified by column chromatography on silical gel (4 g column), eluting with 0- 20% EtOAc/heptane to afford 4-bromo-6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole-3-carbonitrile (0.25 g, 0.67 mmol, 69 % yield) as white solid.
  • the mixture was heated to 80 °C for 3 h. After cooling to rt, the crude reaction was injected into a pre- packed C18 column (50 g), eluting with a gradient of 5 - 80% (0.1% formic acid MeCN)/(0.1% formic acid water) over 10 min. The desired fractions were basified with sat’d aqueous sodium bicarbonate and extracted with EtOAc.
  • the sample (60 mg) was purified via SFC using a Chiralpak IE column (21 x 250 mm, 5 ⁇ m) with a mobile phase of 65% methanol with 0.2% triethylamine using a flowrate of 80 mL/min to generate 22 mg of peak 1 with an ee of >96%, and 23 mg of peak 2 (Example 98) with an ee of >90%.
  • Step 1.7-Bromo-2-chloro-8-fluoro-4-(piperidin-1-yl)quinazoline A vial was charged with 7- bromo-2,4-dichloro-8-fluoroquinazoline (0.75 g, 2.5 mmol, LabNetwork), piperidine (0.25 mL, 2.5 mmol) and acetonitrile (7 mL). The contents was cooled to 0 °C then Hunigs base (1.3 mL, 7.6 mmol) was added dropwise. The reaction mixture was stirred at 0 °C and upon completion, diluted with water and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • a vial was charged with crude 7-bromo-2-chloro-8-fluoro-4-(piperidin-1- yl)quinazoline, (1-((dimethylamino)methyl)cyclopropyl)methanol (0.59 g, 4.6 mmol, Enamine), catalytic DABCO (0.1 equiv), cesium carbonate (2.48 g, 7.6 mmol) and THF/DMF (2:1, 0.2 M).
  • the mixture was heated to 100 °C for 1.5 h. After cooling to rt, the crude material was injected into a pre- packed C18 column (50 g), eluting with a gradient of 5 - 80% (0.1% formic acid MeCN)/(0.1% formic acid water) over 20 min.
  • the impure material was further purified via SFC/MS purification with MeOH as co-solvent at 10-40% gradient to provide (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1H-indazol-4-yl)-2-((1- ((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol as light- yellow solid (8.2 mg, 0.014 mmol, 5.6% yield).
  • reaction mixture was heated to 80 °C for 45 min. After cooling to rt, the reaction mixture was subjected to reverse-phase column chromatography using a C18 column (50 g), 0.1% formic acid in MeCN/H 2 O, gradient 10 - 100% over 10 min. The desired fractions were collected and neutralized with saturated NaHCO 3 solution.
  • Trifluoroacetic acid (0.4 mL, 5.3 mmol) was added, and the reaction was stirred at rt for 1 h. The reaction mixture was slowly quenched with saturated NaHCO 3 solution (3 mL) and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude material was purified by reverse-phase column chromatography using a C18 column (15 g), 0.1% formic acid in MeCN/H 2 O, gradient 5 -100% over 10 min. The desired fractions were neutralized with saturated NaHCO 3 solution and extracted with DCM.
  • reaction mixture was heated to 100 °C and monitored via LCMS. Upon completion, the cooled reaction mixture was injected into a pre-packed C18 column (50 g), eluting with a gradient of 5 - 80% (0.1% formic acid MeCN)/(0.1% formic acid water) over 10 min. The desired fractions were basified with saturated aqueous sodium bicarbonate and extracted with DCM.
  • the mixture was concentrated and redissolved in MeOH (1 mL).
  • the crude material was injected into a pre- packed C18 column (50 g), eluting with a gradient of 5 - 100% (0.1% formic acid MeCN)/(0.1% formic acid water) over 10 min.
  • the desired fractions were basified with saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with EtOAc.
  • Example 119 The sample (Example 119, 41 mg) was purified via SFC using a Chiralcel OD, 21 x 150 mm, 5 ⁇ m, column with a mobile phase of 35% methanol with 0.2% triethylamine using a flowrate of 125 mL/min to generate 11.5 mg of peak 1 with an ee of >99% and 9.5 mg of peak 2 with an ee of >90%. Peak 2 yielded Example 120.
  • KRAS G12D TR-FRET Assay Compounds of interest were prepared in a dose-response titration in DMSO, and 80 nL were added via Labcyte Echo to each well of a 384-well plate (Perkin Elmer 6008280).
  • the His-tagged KRAS G12D protein (Amgen) was diluted to 20 nM in Assay Buffer (20 mM HEPES, pH 7.4, 10 mM MgCl 2 , 50 mM NaCl, 0.1% BSA, 0.01% Tween-20, 10 ⁇ M GDP) and 2 uL was added to the appropriate wells of the 384-well plate. The plate was incubated for 30 minutes at room temperature. Biotinylated KRPep-2d substrate (Amgen) was diluted to 20 nM in Assay Buffer and 2 ⁇ L was added to all wells and incubated for 1 hour at room temperature.
  • Detection Reagent (0.4 nM LANCE Eu-W1024 Anti-6xHis (Perkin Elmer AD0401), 5 nM streptavidin-d2 (Cisbio 610SADLA)) was prepared in Assay Buffer, then 4 ⁇ L was added to the plate and incubated for 1 hour at room temperature. Plates were read using PerkinElmer EnVision (ex: 320 nm, em1: 665 nm, em2: 615 nm) and em1/em2 data was used to generate curve fits using a 4-parameter logistic model to calculate IC 50 values.
  • KRAS G12D Coupled Nucleotide Exchange Assay Purified GDP-bound KRAS protein (aa 1-169), containing both G12D and C118A amino acid substitutions and an N-terminal His-tag, was pre-incubated in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl 2 , and 0.01% Triton X-100) with a compound dose-response titration for 2 h. Following compound pre-incubation, purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 min.
  • assay buffer 25 mM HEPES pH 7.4, 10 mM MgCl 2 , and 0.01% Triton X-100
  • AsPC-1 AsPC-1 (ATCC® CRL-1682TM) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and 1x penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). Sixteen hours prior to compound treatment, AsPC-1 cells were seeded in 96-well cell culture plates at a density of 25,000 cells/well and incubated at 37 °C, 5% CO 2 .
  • a compound dose-response titration was diluted in growth media, added to appropriate wells of a cell culture plate, and then incubated at 37 °C, 5% CO 2 for 2 h. Following compound treatment, cells were washed with ice-cold Dulbecco's phosphate-buffered saline, no Ca 2+ or Mg 2+ (ThermoFisher Scientific 14190144), and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001).
  • RIPA buffer 50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate

Abstract

La présente invention concerne des composés utiles pour l'inhibition de KRAS G12D, G12V, G12A, G12S ou G12C. Ces composés sont représentés par une formule générale (I) : (formule (I)) dans laquelle les variables de la formule (I) sont définies dans la description. La présente invention concerne également des compositions pharmaceutiques comprenant les composés, des utilisations des composés, et des compositions pour le traitement, par exemple, du cancer.
PCT/US2023/062688 2022-02-16 2023-02-15 Composés quinazoline et leur utilisation en tant qu'inhibiteurs de protéines kras mutantes WO2023159087A1 (fr)

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WO2024051763A1 (fr) * 2022-09-08 2024-03-14 深圳福沃药业有限公司 Dérivé hétérocyclique de quinazoline d'inhibiteur de mutation kras pour le traitement du cancer

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